This is our third trial to make comment!


Dear Editor, 7/21/2009

We found the publication of §Ramagopalan et al. in PLoS Genetics (2009) about the regulation of the Multiple Sclerosis (MS)-associated HLA-DRB1*1501 expression and vitamin D very interesting, because it seemed to provide a plausible link between an environmental risk factor for MS, low vitamin D and lack of sunlight exposure, and the major genetic risk factor, the HLA-DR15 haplotype. The data presented in the study suggested that the presence of a specific vitamin D response element is unique to HLA-DRB1*1501. When we looked at the sequences of 21 HLA-DRB1 gene 5’-UTR (5' untranslated region) sequences (DRB1*010101, *010201, *03010101, *03010102, *040301, *07010101, *07010102, *110101, *110102, *110401, *120101, *1217, *130101, *130201, *140501, *1454, *15010101, *15010102, *150201, *15030101, *15030102) that have so far been deposited in the IMGT/HLA Database (http://www.ebi.ac.uk/imgt...), we were, however, disappointed. The VDRE sequence motif (GGGTGGAGGGGTTCA, nt. -85 to -63) that was reported in Ramagopalan et al.’s article is present in most of the 5’-UTR sequences (18/21, see figures 1 and 2, alignments). Only the HLA DRB1*04 and *07 alleles showed a slightly modified VDRE sequence motif (GGGTGGAGAGGGGTCA).

As most of the DRB1 alleles carry the above VDRE sequence motif and most of them are not associated with MS, it is not clear to us how vitamin D deficiency and the HLA-DRB1(*1501) promoter contribute risk to one specific autoimmune disease such as MS. While such a link remains in principle interesting, further investigation is needed to confirm a functional relation between vitamin D levels and the expression of MS-associated HLA-DR alleles.


Thomas M. C. Binder1,, Claudia Schubert1, Roland Martin2 & Thomas H. Eiermann1

1 HLA Laboratory
Department of Transfusion Medicine
Diagnostic Center
University Medical Center Hamburg-Eppendorf
Martinistr. 52
D-20251 Hamburg, Germany
 binder@uke.uni-hamburg.de

2 Center for Molecular Neurobiology
Institute for Neuroimmunology and Clinical MS Research (inims)
Falkenried 94
D-20251 Hamburg, Germany





§ Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton S-M, et al. 2009 Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D. PLoS Genetics 5(2): e1000369. doi:10.1371/journal.pgen.1000369

Figure 1 (Courier New, 6)



VDRE ← 5’-UTR | Exon 1 →
-71 -61 -51 -41 -31 -21 -11 -1 |1 10
DRB1*010101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*010201 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*03010101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*03010102 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*040301 TGTGGGTGGAGA GGGG.TCATA GTTCTCCCTG AGTGAGACTC ACCTGCTCCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*07010101 TGTGGGTGGAGA GGGG.TCATA GTTCTCCCTG AGTGAGACTC ACCTGCTCCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*07010102 TGTGGGTGGAGA GGGG.TCATA GTTCTCCCTG AGTGAGACTC ACCTGCTCCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*110101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*110102 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*110401 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*120101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*1217 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*130101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*130201 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*140501 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*1454 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTGCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*15010101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*15010102 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*150201 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*15030101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*15030102 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
GGGTG GA GGGGTTCA






Figure 2



VDRE ← 5’-UTR | Exon 1 →
-71 -61 -51 -41 -31 -21 -11 -1 |1 10
DRB1*010101 TGTGGGTG..GA GGGGTTCATA GTTCTCCCTG AGTGAGACTT GCCTGCTTCT CTGGCCCCTG GTCCTGTCCT GTTCTCCAGC |ATGGTGTGTC
DRB1*010201 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*03010101 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*03010102 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*040301 --------GA-- ----.----- ---------- ---------C A------C-- ---------- ---------- ---------- |----------
DRB1*07010101 --------GA-- ----.----- ---------- ---------C A------C-- ---------- ---------- ---------- |----------
DRB1*07010102 --------GA-- ----.----- ---------- ---------C A------C-- ---------- ---------- ---------- |----------
DRB1*110101 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*110102 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*110401 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*120101 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*1217 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*130101 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*130201 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*140501 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*1454 --------..-- ---------- ---------- ---------- -------G-- ---------- ---------- ---------- |----------
DRB1*15010101 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*15010102 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*150201 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*15030101 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
DRB1*15030102 --------..-- ---------- ---------- ---------- ---------- ---------- ---------- ---------- |----------
GGGTG GA GGGGTTCA